Abstract

Herpesviruses employ sophisticated immune evasion strategies to establish lifelong infections, subverting type I interferon (IFN-I) responses critical for antiviral defense. However, their adaptive mechanisms across species remain poorly characterized. Using duck plague virus (DPV)—an avian alphaherpesvirus model—we identify a cooperative immune evasion axis wherein ICP27 orchestrates UL55-mediated immunosuppression through dual regulatory mechanisms: its RNA-binding domain (RGG) facilitates UL55 mRNA nuclear export, while its C-terminal domain (CTD) stabilizes UL55 protein via direct interaction. This partnership enables synergistic suppression of IFN-I signaling—co-expression of ICP27 and UL55 inhibits Poly(I:C)-induced immune genes (IFN-β, Mx, OASL, IL-6) more potently than either protein alone. UL55 functions as a precision-targeted IFN-I antagonist, selectively degrading RIG-I and IRF7 through proteasomal pathways—confirmed by proteasome inhibitor rescue (MG132), structural modeling (AlphaFold), and binding assays (Co-IP). Evolutionarily, UL55 homologs (DPV, Herpes simplex virus type 1 [HSV-1], Varicella zoster virus [VZV]) conserve RIG-I targeting but diverge in IRF3/IRF7 regulation—adaptations shaped by UL55 sequence divergence (38.68% identity) and host biology (e.g., waterfowl IRF3 deficiency). This work establishes ICP27-UL55 as a key regulatory axis in herpesviral immune evasion and redefines UL55 as a conserved yet adaptable immunosuppressor in Alphaherpesvirinae.